Method of removing phosphorus-containing wastes generated upon receipt of salts of omega-amino-(c2- c6)alkylidene-1 - hydroxy-1,1-bisphosphonic acid, and the precipitated mixture of salts containing calcium and phosphorus

 

(57) Abstract:

The invention relates to a method of removing phosphorus-containing wastes generated upon receipt of salts of omega-amino-(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonic acids, which includes the stages of: a) contacting the aqueous medium after separation of the salts of omega-amino-(C2-C6)alkylidene-1-hydroxy-1,1-bis-phosphonic acid with a compound of chloride of calcium, taken in an amount of 2-10 wt. hours at 100 rpm.h. environment; (b) contacting the solution from step (a) with calcium oxide, taken in an amount sufficient to cause precipitation of salts containing calcium and phosphorus, (C) contacting the mixture from step (b) with acid to bring the pH of the water portion of the mixture to a value of 6-8, and cause the precipitation of these salts containing calcium and phosphorus, (d) separation of a mixture of salts containing calcium and phosphorus. The invention relates also to a precipitated mixture of salts containing calcium and phosphorus. The salts can be removed by burning, burial in soil or use as fertilizer. 2 C. and 8 C.p. f-crystals, 3 ill.

The invention concerns a method of removing phosphorus-containing substances, POxalendronate and side-products of alendronate from neoc the deposits and neutralization using CCl2and CaO and filtering.

The level of technology.

Alendronate sodium trihydrate monosodium salt of 4-amino-1-hydroxybutylidene-1-bisphosphonate acid is a promising new tool to combat bone resorption in diseases of the bones, including osteoporis, especially for women in postclimacteric period. This compound, its use and method of obtaining described in U.S. patent 4922007 and 5019651 owned by the company Merck & co, Inc."

In the industrial processes of alendronate sodium, described in these patents, is formed as a waste of large amounts of soluble phosphorus-containing substances (POx), including sodium salts of phosphates, phosphites and pyrophosphates.

However, the equipment for processing juicy water (WWTP) when the clock work, you can process waste water containing about 1-10 ppm (mg/l) phosphorus per liter of wastewater.

However, in the process of synthesis of alendronate can get up to 500 mg of phosphorus in the form of POxper liter of wastewater per day, which significantly pruyser in many geographical regions, the maximum permissible limits for wastewater treatment and effluent discharge.

One common method to this problem involves the transmission of a stream of sulfoxylate (MSC).

However, this method suffers the disadvantage that the active sludge daily can process only a small number of POxand MSC. For example, at a load of 1000 pounds (454 kg) for substances having biological oxygen demand (BOD), activated sludge can usually be absorbed from wastewater using as food for microorganisms, only 5-10 pounds per day (2,27-4,54 kg/day) phosphorus.

It would therefore be highly desirable to find a way to extract and re-use (in this process) phosphorus-containing substances POxpresent in the waste water, environmentally safe, efficient and cost effective manner.

A brief description of the figures.

Fig. 1 illustrates the General scheme of chemical reactions bisphosphonates process of receiving alendronate sodium.

Fig. 2 illustrates a General process flow bisphosphonates process of receiving alendronate sodium.

Fig.3 illustrates the stage of deposition of calcium and phosphorus removal.

Summary of invention.

It was found that the residual phosphorus-containing substances, POxlocated in the raw water the mother solution, om deposition, including the addition of calcium chloride, then adding lime, followed by neutralization and filtration. The filter cake containing the crude POxthat also contains the remains of alendronate and by-products of its synthesis, it is possible to remove a variety of environmentally acceptable methods, for example by burying in the soil, incineration or recycling of phosphorus as fertilizer.

In this invention a method is proposed, comprising the following stages;

a) contacting the aqueous medium with a pH of approximate 4-8, for example, a solution containing salt, such as sodium, potassium, calcium, omega-amino (C2-C6)alkyliden-1 hyroxy-1,1-bisphosphine acid, methanesulfonate, phosphorous acid and phosphoric acid, with a compound of calcium chloride in the amount of 2-10 weight. including calcium chloride, taken in the form of the anhydrous salt at about 100. including environment at room temperature;

(b) contacting the specified environment from stage (a) with calcium oxide, taken in sufficient quantity to increase the pH to about 10-12 and cause precipitation of salts containing calcium and phosphorus;

(C) contacting the above-mentioned mixture from stage (b) with an acid such as hydrochloric acid, sulfuric acid, with the aim of bringing RSTR;

(d) the Department specified precipitated mixture of salts containing calcium and phosphorus from the water environment.

Brief description of the invention and the preferred variants of the embodiment of the invention.

General chemical scheme of the process for receiving alendronate sodium, as shown in Fig. 1, includes three stages: reaction bisphosphonate, water quenching with controlled pH, and the stage of hydrolysis and crystallization of the crude product. The process can be performed or periodic, or continuous manner, using standard equipment.

In response bisphosphonate (see U.S. patent 4922007) gamma-aminobutyric acid (GABA) is reacted with phosphorus trichloride (PCl3) and phosphorous acid (H3PO3in methansulfonate (MSC) as solvent at the temperature for about 0.5 to 3 hours the Reaction is usually carried out at atmospheric pressure. As can be seen from Fig. 1, the initial reaction product is a pyrophosphate (PP) and multidimensional predecessors of alendronate (not shown).

Then the reaction mixture is quenched in water, at a controlled pH, maintaining a pH in the range from about 4 to 7 using aqueous solution of caustic soda. Then set the pH of the th 1 to 4 ATM, at a temperature of from about 100 to 150oC for from about 2 to 30 hours up to almost complete conversion of pyrophosphate and multidimensional predecessors in alendronate sodium. Minor remaining part that is not turned in alendronate sodium, is called "by-products of the synthesis of alendronate".

Crystallization of the crude product is carried out, cooling the hydrolysis mixture of about 10-60oC, for example, up to 50oC, and establishing a pH of about 4-5, preferably using the interval from 4.2 to 4.7 by adding an aqueous solution of caustic soda or hydrochloric acid, resulting in the crystalline alendronate sodium trihydrate), which is filtered, collected, cleaned and processed.

General technological scheme of the process for receiving alendronate sodium is shown in Fig. 2.

As can be seen from the figure, the initial mixture GABA prepared from a mixture of GABA, MSC and H3PO3, and served mixture together with PCl3in the reaction vessel for the reaction of bisphosphonate to obtain pyrophosphate (PP).

After the stage of bisphosphatase the reaction mixture is reacted with an aqueous solution of acoustic soda at the stage of extinction at a controlled pH of from 4 to 7 of obree and temperature for the next stage of the hydrolysis with the formation of alendronate sodium.

Hydrolysis mixture is cooled, establish a pH in the range from 4 to 5, and the trihydrate of alendronate of moonacre precipitates in the form of crude crystallization mass.

The crude crystallized alendronate sodium is filtered, the wet precipitate was washed with a minimum amount of cold demineralized (DM) water, separated from the crude mother liquor and then subjected to the stage of pure crystallization from water.

Pure crystalline alendronate sodium, having a pharmaceutically acceptable quality, collect and grind, getting clean, loose shredded alendronate sodium, which can be further processed to pharmaceutical dosage formulations.

Gaseous by-products from the stage of bisphosphonate, consisting mainly of HCl, PCl3and couples with stage quenching and crystallization of the crude product containing traces of dimethyl disulfide (DMDS), served in a scrubber containing water, caustic soda and sodium hypochlorite, with the receiving process wastewater stream containing primarily a mixture of Na2HPO3, Na2HPO4, Na3PO3, Na3PO4and sodium chloride, which can Vigo to pass through a layer of activated charcoal, to remove dimethyl sulfide (DMDS), and the filtrate collecting tank for deposition of POxand alendronate. POxcan be completely or partially removed using the technique of deposition by using CaCl2and Ca), as described here.

Untreated uterine solutions first pass through a layer of activated charcoal to remove the dimethyl disulfide (DMDS), and then served in the tank for the deposition, which served CaCl3, lime, and which is regulated by pH, as shown in Fig.3.

A new aspect of the present invention is a new method of processing (reuse) removing the resulting purified uterine fluids.

The crude mother liquor (MLS) contains about 5-10 wt.% phosphates and phosphites, in the form of POx, 22-25% GMT, 5% NaCl, 1-2% GABA, 0.5-1% alendronate sodium and side-products of its synthesis and 60-65% of water.

At the initial stage add connection CaCl2in the amount of from about 2 to 10 wt.% on the volume of the mother liquor and usually 2-4% weight/vol., taken in the form of anhydrous CaCl2. Usually CaCl3for facilities used in the form of uranyl, although you can also use more expensive anhydrous CaCl2. The purpose of adding CaCl2in the beginning proective salts, containing calcium and phosphorus.

Then add CaO (lime) in sufficient quantity), usually 3-7% weight/volume, and usually about 5% weight/volume to dissolve in the mother solution and to obtain a pH of about 10-12 to facilitate the subsequent deposition of POxconnections.

After that, the mixture is neutralized by adding, for example, hydrochloric acid to reduce the pH to about 6 to 8, for example, up to 7. The resulting suspension is stirred for about 2-4 hours, to ensure the maximum possible precipitation of all substances POxin the mother solution.

Exception adding CaCl2or stage neutralization leads to a decrease in the degree of extraction of POx. The degree of extraction of POxapproximately 90-95 +% is achieved when using the method proposed in the present invention. However, the addition of only one CaO gives the degree of recovery of about 60%. Moreover, the use of CaCl2and CaO without stage neutralization gives the degree of recovery of about 88%.

An additional advantage of this method of removal POxis that the residual alendronate sodium, which is an active ingredient of medicines, as well as by-products of the synthesis of alendronate also selek is the CaO same time, the suspension is filtered and washed on the filter with water, preferably demineralized (DM) water. The filtrate is removed for installation for wastewater treatment or regeneration of the solvent, or, if the content of POxquite low, on a separate stage of decomposition by bacteria for processing ORT methansulfonate (MSC) before filing for the installation of wastewater treatment.

For biodegradation MSCS can use stage microbiological decomposition using akklimatizirovannoi culture of sludge in which the sludge serves the increasing concentration of MSC in waste water while maintaining the pH, BOP, time hydraulic processing and the density of the sludge is optimal for this process.

Deposited on the filter cake POxthat contains mainly CaHPO3, CaHPO4and alendronate calcium, can be dried and used for soil, send for incineration or to return to the factory for the production of fertilizers extraction of phosphorus compounds that are fashionable to use.

With the average performance of the process can be carried out in periodic mode. However, the removal process POxcan also be arranged as a continuous process during its holding in large scale is in pH. An alternative reagent, which can be used for deposition of POxis Al(OH)3but it only adds a new cation to the already complex ceiling of waste. In addition, it was found that Al+++less effective than Ca++to remove POxfrom this stream.

The described method of extracting POxcan also be used in other processes bisphosphonate, where as starting substances can be used appropriate amino acids to obtain the following omega-amino (C2-C6-alkylidene-1,1-bisphosphonic acid, -amino-1-hydroxypropane-1,1-bisphosphonic acid, 5-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and 6-amino-1-hydroxybenzylidene-1,1-bisphosphonic acid. The term "omega-amino" is used here to indicate the presence of an amino group at the terminal carbon atom alkylidene circuit at the opposite end from bisphosphatase carbon atom.

The following examples illustrate the implementation of the invention as it is imagined by the inventors.

Example 1.

Adding CaCl2and Ca) and neutralization

To 1 l of treated activated carbon to remove DMDS) untreated uterine ro calcium (CaCl2) and stirred for 15 min (pH4, T=20-25oC).

Then add 50 g of lime (CaO and quickly stirred for 30 min (pH 12). The pH value and the temperature is typically increased to about 12 and 45oC, respectively.

After this was added concentrated HCl (36%) to bring the pH of the mixture to about 7. To stabilize the pH at level 7, it may be necessary to add HCl several times. This requires approximately 75 ml of 36% HCl. Neutralization was discontinued when the pH value is about 7 remained stable for at least 10 minutes, the temperature Rise was usually minimal (5oC).

The mixture was left for stirring for 5 min, then milled through filter paper Whatman # 4 on a Buechner funnel under vacuum. The filter cake was washed 2-5 volumes of DM water to remove residual MSC and NaCl from the precipitate on the filter. Wash water was combined with the filtrate to highlight the MSC. Total time filtering usually was about 1 o'clock

The filtrate can be treated using activated sludge system described above. Sediment CaPOxaccumulated for subsequent removal.

The removal efficiency (extraction) PO2(mixing) + 50 g/l lime (mixing) + regulation of pH using HCl to pH 7, followed by filtration and washing DM water.

Repetition of the above process stages without adding CaCL2and neutralization gave the degree of extraction of POxonly about 60%.

Repetition of the above process without the final stage neutralization pH gave the degree of extraction of POxonly about 88%.

1. Method of removing phosphorus-containing wastes generated upon receipt of salts omega-amino(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonic acids, characterized in that it comprises the stages of: a) contacting the aqueous medium, after separation of the salts omega-amino(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonic acids and containing salt residue omega-amino(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonate acid, salts of methansulfonate, phosphoric and phosphonic acids, with a compound of chloride of calcium, taken in an amount of 2 to 10 wt. hours at 100 rpm. including the environment, and the number of connections of calcium chloride calculated on the basis of anhydrous calcium chloride; (b) contacting the specified solution from stage (a) with calcium oxide, taken in an amount eno from stage (b) with an acid, to bring the pH of the water portion of the mixture to a value of about 6 to 8 and to cause the deposition of these salts containing calcium and phosphorus; (d) the Department specified precipitated mixture of salts containing calcium and phosphorus from the water environment.

2. The method according to p. 1, in which the specified omega-amino(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonic acid is chosen from 4-amino-1-hydroxybutylidene-1,1-bisphosphonate acid, 2-amino-1-hydroxyisobutyrate-1,1-bisphosphonate acid, 3-amino-1-hydroxypropylamino-1,1-bisphosphonate acid, 5-amino-1-hydroxybutylidene-1,1-bisphosphonate acid and 6-amino-1-hydroxybenzylidene-1,1-bisphosphonate acid.

3. The method according to p. 2, in which the specified omega-amino(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonic acid is 4-amino-1-hydroxybutane-1,1-bisphosphonate acid.

4. The method according to p. 1, in which these salts omega-amino(C2-C6)alkylidene-1-hydroxy-1,1-bisphosphonate acid, methanesulfonate, phosphorous and phosphoric acids are sodium salts.

5. The method according to p. 1, wherein said calcium chloride is hexahydrate form.

6. The method according to p. 1, wherein said calcium chloride in stage (a) of prisutstvie (b) is approximately 10 - 12.

8. The method according to p. 1, which is added to stage (C) acid is a hydrochloric acid.

9. The precipitated mixture of salts containing calcium and phosphorus, obtained by the method according to p. 1.

10. The precipitated mixture of salts on p. 9 containing alendronate.

 

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